The role of gender in the progression of diabetic peripheral neuropathy (DPN) is uncertain. Some studies have shown that the incidence of DPN may be lower in premenopausal women than in post-menopausal women or men. However, the reason is unclear. Research has shown that estrogen (E2) protects against nerve injury, promotes nerve regeneration, induces sensory neuritogenisis in vitro, and increases sensory innervation density in vivo. Previous experiments from our lab have shown that E2 increases Angiotensin II Type 2 receptor (AT2) in sensory dorsal root ganglia, and this receptor is implicated in axon regeneration and sprouting. The objective of experiments proposed in this training program is to determine if E2 is beneficial in slowing the progression of DPN. The central hypothesis is that E2 prevents sensory nociceptor degeneration caused by diabetes by elevating AT2 expression in dorsal root ganglion neurons. In the first aim, we will determine if endogenous reproductive hormones modulate DPN progression. Experiments will characterize pathologies in footpad cutaneous innervation in cycling and ovariectomized (OVX) diabetic rats, and correlate these with behavioral changes in sensitivity. The second aim will clarify whether exogenously administered E2 prevents sensory nociceptive fibers degeneration during DPN. OVX diabetic animals will receive E2 replacement and changes in behavioral responses and nociceptive innervation will be compared to untreated OVX diabetic rats. The third aim will determine if estrogen prevents degeneration of sensory nociceptive fibers by upregulating AT2. This hypothesis will be tested by examining AT2 protein expression in OVX and OVX+ E2 diabetic animals and determining if an AT2 antagonist impairs E2's beneficial effects. These studies will provide new information regarding the relationship between E2 and DPN, and may aid in the formation of new therapeutic approaches for treating DPN. PUBLIC HEALTH RELEVANCE: Diabetic peripheral neuropathy affects nearly 50% of the diabetic population, but may be less severe in premenopausal women than in other groups. An understanding of how estrogen may prevent or attenuate diabetic peripheral neuropathy may provide new insight into possible therapeutic strategies.